Weight Reduction Medications for People With Overweight or Obesity

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Adults with extreme overweight or obesity are often treated with lifestyle modifications, bariatric surgery, or a small number of FDA-approved drugs. Researchers studied whether antidiabetic and other drugs could help weight loss efforts.

Phentermine-topiramate and glucagon-like peptide-1 (GLP-1) receptor agonists such as semaglutide are effective for weight loss in adults with overweight and obesity,  according to findings published in the Lancet.  

Researchers conducted a systematic review and meta-analysis of randomized controlled trials analyzing several weight loss medications for adults with overweight and obesity, searching PubMed, Embase, and the Cochrane Library (CENTRAL) from inception to March 23, 2021. A total of 143 eligible trials with 49,810 overweight or obese adults were included in the study.

Phentermine-topiramate showed a higher likelihood of  treatment discontinuation due to adverse events, whereas GLP-1 receptor agonists like semaglutide had less adverse events resulting in discontinuation of therapy.

In addition to phentermine-topiramate and GLP-1 receptor agonists, other medications analyzed in the study included pramlintide, sodium-glucose transport protein 2 (SGLT2) inhibitors, naltrexone-bupropion, orlistat, metformin, and levocarnitine. Many of these drugs were compared to either lifestyle modifications alone or against each other in  randomized controlled trials.

Outcomes analyzed by the investigators included percentage body weight change from baseline to final follow-up, the number of study participants who reduced body weight by 5% or more, adverse events which led to discontinuation of treatment, change in quality-of-life score, and the amount of weight regained after treatment discontinuation.

Investigators considered the total number of gastrointestinal events, changes in body image score, depression, and anxiety as ‘important but not crucial” measures in the study. Least important outcomes, as deemed by the investigators, included changes in low-density lipoprotein (LDL) cholesterol, systolic blood pressure, glycated hemoglobin (HbA1C) and absolute body weight from baseline to final follow-up.

All drugs except levocarnitine were associated with a body weight change from baseline, with phentermine-topiramate the most effective (odds ratio (OR) of ≥ 5% weight reduction, 8.02, 95% CI, 5.24 to 12.27) followed by GLP-1 receptor agonists (OR 6.33, 95% CI, 5.00 to 8.00). All drugs except pramlintide reduced body weight by 5% or more compared with lifestyle modifications alone. Metformin, SGLT2 inhibitors, and pramlintide were not associated with a reduction in body weight of greater than 10%, whereas the other medications did.

Naltrexone-bupropion, GLP-1 receptor agonists, and phentermine-topiramate more than doubled weight loss by 5% and 10%.  All three medications showed a moderate increase in quality-of-life scores, but naltrexone-bupropion and phentermine-topiramate were most likely to have adverse events leading to discontinuation.

In a post-hoc analysis, semaglutide was associated with the largest weight loss percentage and the greatest likelihood of losing weight by 5% and 10% or more.

“Limitations of our review include the absence of individual patient data pooling, which particularly reduced the precision of synthesis for subgroups effects,” according to the study authors. Other limitations included a variation in population characteristics and duration of follow-up.

“Phentermine-topiramate represents a well-established weight-lowering treatment that is approved for this indication only in the USA,” the study authors concluded. “Our post-hoc analysis supports the use of semaglutide as a new therapeutic option for weight management, given the superior weight-lowering effects and intermediate risk of adverse events leading to treatment discontinuation.”

Disclosure: One study author declared grant support from an outside university program. Please see the original reference for a full list of authors’ disclosures.


Shi Q, Wang Y, Hao Q, et al. Pharmacotherapy for adults with overweight and obesity: a systematic review and network meta-analysis of randomized controlled trials. Lancet. Published online December 8, 2021. doi:10.1016/S0140-6736(21)01640-8